Background To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

中文翻译：

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基因组改变对HER2 +胃癌患者HER2治疗期间拉帕替尼治疗结果和无细胞基因组格局的影响。

背景技术通过无细胞基因组学确定拉帕替尼治疗患者中应答者的预测标记，并证明拉帕替尼治疗期间的分子变化。患者和方法我们前瞻性地评估了拉帕替尼联合卡培他滨和奥沙利铂作为一线新辅助疗法在先前未经治疗，HER2过表达的晚期胃癌患者中的疗效。通过同时对肿瘤和血液样本进行免疫组织化学和下一代测序（NGS）进行了平行的生物标志物研究。结果在7/32例患者中确认了完全缓解（21.8％），其中2例接受了根治性手术，并经病理证实为完全缓解。观察到十五部分反应（46.8％），导致总反应率为68.6％。16个肿瘤标本的NGS表明，最常见的同时出现的拷贝数变化是CCNE1扩增，CCNE1扩增存在于40％的HER2 +肿瘤中。CCNE1扩增与对HER2靶向治疗缺乏反应之间的关系趋于统计学显着性（无反应者中有66.7％，而具有CCNE1扩增者中有22.2％的反应者； P = 0.08）。与低水平ERBB2扩增的患者相比，NGS较高水平的ERBB2扩增的患者对治疗更有可能产生反应（P = 0.02）。cfDNA的分析表明，血浆中可检测到的ERBB2拷贝数扩增可预测应答（100％，应答率），血浆检测到的基因组改变的变化与拉帕替尼的敏感性和/或耐药性相关。疾病进展的后续cfDNA基因组学研究表明，出现了其他基因组畸变，例如MYC，EGFR，FGFR2和MET扩增。结论本研究表明，HER2 + GC患者根据超出ERBB2的伴随基因组畸变做出不同反应，NGS或cfDNA引起的高ERBB2扩增可作为患者选择的积极预测指标，并且在靶向药物治疗期间肿瘤基因组变化发生显着变化。